Thyroid-stimulating hormone (TSH) is a heterodimeric glycoprotein hormone that regulates thyroid homeostasis by regulating the growth, proliferation and function of thyroid follicular cells. Cellular responses to TSH are mediated via the TSH receptor (TSHR) which is a distinct seven transmembrane-spanning receptor. TSHR is the major regulator of thyroid gland function and is expressed in tissues other than the thyroid including adipocyte (fat) precursor cells, adipocytes, fibroblasts, immune cells and bone. Activation of TSHR by its endogenous hormone TSH is required for normal thyroid homeostasis but may also regulate the function of these other tissues/cells.
TSHR is involved in the pathogenesis of several diseases. In Graves' disease, TSHR-stimulating antibodies (TSAbs) activate TSHR, mimicking the effects of TSH. This results in hyperthyroidism by activating TSHRs on thyroid cells and in Graves' orbitopathy (or ophthalmopathy or thyroid eye disease) by activating TSHRs on cells in the retro-orbital space behind the eyes. TSH also stimulates the growth, proliferation and metastasis of thyroid cancer cells by activating TSHRs on cancer cells. Indeed, most patients after surgery for thyroid cancer are treated with thyroid hormone to suppress TSH levels in the blood. TSHR exhibits basal signaling activity, that is, signaling activity in the absence of TSH or TSAbs.